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Mycobacterium tuberculosis Lsr2 is a global transcriptional regulator required for adaptation to changing oxygen levels and virulence

ABSTRACT: To survive a dynamic host environment, Mycobacterium tuberculosis must endure a series of challenges from reactive oxygen and nitrogen stress, to drastic shifts in oxygen availability. The mycobacterial Lsr2 protein has been implicated in reactive oxygen defense via direct protection of DNA. To examine the role of Lsr2 in pathogenesis and physiology of M. tuberculosis, we generated a strain deleted for lsr2. Analysis of the M. tuberculosis Δlsr2 strain demonstrated that Lsr2 is not required for DNA protection, as this strain was as equally susceptible as the wild-type to DNA-damaging agents. The lsr2 mutant did display severe growth defects under normoxic and hyperoxic conditions, but was not required for growth under low oxygen conditions. However, it was also required for adaptation to anaerobiosis. The defect in anaerobic adaptation led to a marked decrease in viability during, as well as a lag in recovery from, anaerobiosis. Gene expression profiling of Δlsr2 under aerobic and anaerobic conditions in conjunction with published DNA binding-site data indicate that Lsr2 is a global transcriptional regulator controlling adaptation to changing oxygen levels. The Δlsr2 strain was capable of establishing an early infection in the Balb/c mouse model; however, it was severely defective in persisting in the lungs and caused no discernible lung pathology. These findings demonstrate M. tuberculosis Lsr2 is a global transcriptional regulator required for control of genes involved in adaptation to extremes in oxygen availability and is required for persistent infection.

ORGANISM(S): Mycobacterium tuberculosis Mycobacterium tuberculosis H37Rv Mycobacterium tuberculosis CDC1551

PROVIDER: GSE57948 | GEO | 2014/05/24

SECONDARY ACCESSION(S): PRJNA248476

REPOSITORIES: GEO

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Project description:Saccharomyces cerevisiae is unique among yeasts for its ability to grow rapidly in the complete absence of oxygen. S. cerevisiae is therefore an ideal eukaryotic model to study physiological adaptation to anaerobiosis. Recent transcriptome analyses have identified hundreds of genes that are transcriptionally regulated by oxygen availability but the relevance of this cellular response has not been systematically investigated at the key control level of the proteome. Therefore, the proteomic response of the S. cerevisiae to anaerobiosis was investigated using metabolic stable isotope labeling in aerobic and anaerobic glucose-limited chemostat cultures, followed by proteome analysis to relatively quantify protein expression. Using independent replicate cultures and stringent statistical filtering, a robust dataset of 474 quantified proteins was generated, of which 249 showed differential expression levels. While some of these changes were consistent with previous transcriptome studies, many responses of S. cerevisiae to oxygen availability were hitherto unreported. Comparison of transcriptome and proteome from identical cultivations yielded strong evidence for post-transcriptional regulation of key cellular processes, including glycolysis, amino-acyl tRNA synthesis, purine-nucleotide synthesis and amino-acid biosynthesis. The use of chemostat cultures provided well-controlled and reproducible culture conditions, which are essential for generating robust datasets at different cellular information levels. Integration of transcriptome and proteome data led to new insights in the physiology of anaerobically growing yeast that would not have been apparent from differential analyses at either the messenger RNA or protein level alone, thus illustrating the power of multi-level studies in yeast systems biology. Protein levels versus transcript level: Systematic analysis of the control levels at which the yeast response to anaerobiosis takes place was performed using previously published transcript data obtained from yeast cultures grown under strictly identical conditions as described for the current proteome analysis. Affymetrix microarrays from five aerobic and four anaerobic independent culture replicates were used for this analysis. These comparison data are summarized in the table below. These array data are publicly available at the gene expression repository Gene Expression Omnibus under accession number GSE4804. Keywords: proteomic, nanoflow-LC-MS/MS

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Mycobacterium tuberculosis Lsr2 is a global transcriptional regulator required for adaptation to changing oxygen levels and virulence

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